Mechanism of action
Melphalan flufenamide, also known as melflufen, is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside cancer cells.
Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and is immediately hydrolyzed by peptidases to release an entrapped hydrophilic alkylator payload. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the increased intracellular alkylator concentration. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of angiogenesis and metastatic process in preclinical studies.
- Peptidases are expressed in several cancers, including solid tumors and hematologic malignancies.6-8
- Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity.1,3
- Once inside the myeloma cell, the activity of melflufen is determined by its immediate cleavage by peptidases into hydrophilic alkylator payloads that are entrapped.3-5
- In vitro studies suggest that melflufen is 50-fold more potent than melphalan in myeloma cells due to the increase of intracellular alkylator concentration.1,3
- Meflufen rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells.1,2
- Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, in vitro as well as overcomes p53-deficiency-mediated resistance in myeloma cell lines, a common mechanism of resistance to antimyeloma therapies.1,2
- Melflufen also has demonstrated inhibition of angiogenesis and metastatic process in preclinical studies.1,9,10
Chauhan D, Ray A, Viktorsson K, et al. In vitro and In vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clinical Cancer Research. 2013;19(11):3019-3031.
Ray A, Ravillah D, Das DS, et al. A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. British Journal of Haematology. 2016;174(3):397-409.
Wickström M, Nygren P, Larsson R, et al. Melflufen – a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017;8(39).
Wickström M, Viktorsson K, Lundholm L, et al. The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan. Biochemical Pharmacology. 2010;79(9):1281-1290.
Gullbo J, Wickström M, Tullberg M, et al. Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrugJ1. Journal of Drug Targeting. 2003;11(6):355-363.
Hitzerd SM, Verbrugge SE, Ossenkoppele G, Jansen G, Peters GJ. Positioning of aminopeptidase inhibitors in next generation cancer therapy. Amino Acids. 2014;46(4):793-808.
Moore HE, Davenport EL, Smith EM, et al. Aminopeptidase inhibition as a targeted treatment strategy in myeloma. Molecular Cancer Therapeutics. 2009;8(4):762-770.
Wickström M, Larsson R, Nygren P, Gullbo J. Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Science. 2011;102(3):501-508.
Strese S, Wickström M, Fuchs PF, et al. The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo. Biochemical Pharmacology. 2013;86(7):888-895.
Byrgazov K, et al. Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide. Ther Adv Med Oncol. 2020 Jul 29;12:1758835920937891. doi: 10.1177/1758835920937891